Ishida A, Trescher W H, Lange M S, Johnston M V
Department of Neurology, Johns Hopkins University, School of Medicine, and The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA.
Brain Dev. 2001 Aug;23(5):349-54. doi: 10.1016/s0387-7604(01)00237-6.
Nitric oxide mediates glutamate-induced excitotoxicity associated with cerebral hypoxia-ischemia through production in the brain by several isoforms of nitric oxide synthase (NOS). We examined the influence of the selective neuronal NOS inhibitor, 7-nitroindazole (7-NI), on brain NOS activity and its neuroprotective effects against cerebral hypoxic-ischemic injury in the postnatal day (PND) 7 rat. In the first set of experiments, 7-NI (50 mg/kg) administered intraperitoneally (i.p.) transiently inhibited NOS activity to 40% below the vehicle control level at 1 h after injection (P<0.001, analysis of variance (ANOVA)). In contrast, 7-NI (100 mg/kg, i.p.) inhibited NOS activity to 56% below the control level at 1 h with prolonged suppression of NOS activity at 3, 6, 9 and 12 h after injection. Two-factor ANOVA revealed an overall effect on NOS activity of 7-NI treatment (P<0.001) and time after injection (P<0.001). In the second set of experiments, 7-NI (50, 100 mg/kg) or an equal volume of vehicle was administered after unilateral carotid artery ligation, but 30 min before hypoxia in PND 7 rats. 7-NI (100 mg/kg) significantly protected against cerebral hypoxic-ischemic injury (100 mg/kg of 7-NI, 1.7+/-1.0% damage; control, 8.7+/-1.6%,P<0.05). 7-NI administered 15 min after cerebral hypoxia-ischemia was not neuroprotective. The data suggest that the protective effect of 7-NI is dose dependent, and is related to the duration of suppressed NOS activity.
一氧化氮通过几种一氧化氮合酶（NOS）同工型在脑内产生，介导与脑缺氧缺血相关的谷氨酸诱导的兴奋性毒性。我们研究了选择性神经元NOS抑制剂7-硝基吲唑（7-NI）对出生后第7天（PND 7）大鼠脑NOS活性的影响及其对脑缺氧缺血损伤的神经保护作用。在第一组实验中，腹腔注射（i.p.）50 mg/kg的7-NI在注射后1小时将NOS活性短暂抑制至低于溶剂对照水平40%（P<0.001，方差分析（ANOVA））。相比之下，100 mg/kg（i.p.）的7-NI在注射后1小时将NOS活性抑制至低于对照水平56%，并在注射后3、6、9和12小时持续抑制NOS活性。双因素方差分析显示7-NI处理对NOS活性有总体影响（P<0.001），且注射后时间也有影响（P<0.001）。在第二组实验中，在PND 7大鼠单侧颈动脉结扎后但缺氧前30分钟给予7-NI（50、100 mg/kg）或等体积的溶剂。100 mg/kg的7-NI显著保护大鼠免受脑缺氧缺血损伤（100 mg/kg的7-NI，损伤率为1.7±1.0%；对照组为8.7±1.6%，P<0.05）。在脑缺氧缺血后15分钟给予7-NI没有神经保护作用。数据表明7-NI的保护作用是剂量依赖性的，并且与NOS活性被抑制的持续时间有关。
